"Why our proteins have to die so we shall live" - A Lecture by Aaron Ciechanover

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Video in TIB AV-Portal: "Why our proteins have to die so we shall live" - A Lecture by Aaron Ciechanover

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"Why our proteins have to die so we shall live" - A Lecture by Aaron Ciechanover
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"Warum unsere Proteine sterben müssen, damit wir leben können" - Ein Vortrag von Aaron Ciechanover
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Prof. Dr. Aaron Ciechanover (Haifa) spricht über seine Forschungen an dem Peptid Ubiquitin, das im Organismus nicht mehr benötigte Proteine abbaut. Diese intrazelluläre 'Müllabfuhr' ist notwendig für die Gesunderhaltung unseres Körpers. Die Erforschung des Ubiquitin-Systems ist Grundlage für die Entwicklung moderner Medikamente, u. a. für die Krebsbekämpfung. Aaron Ciechanover erhielt im Jahre 2004 den Nobelpreis für Chemie zusammen mit Avram Hershko und Irwin Rose.
Prof. Dr. Aaron Ciechanover (Haifa) speaks about his research on the peptide ubiquitin which is necessary for the protelolysis in our organism. This intracellular 'waste collection' is necessary for the health of our body. The investigation of the ubiquitin proteasome system is an important basis for the development of modern drugs like for instance for cancer control. Aaron Ciechanover is the Nobel laureate in chemistry in 2004 together with Avran Hershko and Irwin Rose.
Keywords Ciechanover, Aaron Nobelpreisträger Medikament Krebs Ubiquitin-Proteasome-System Proteasome Ubiquitin Ligase Lysosomen Proteolyse Eiweissabbau interzellularer Proteinabbau Biochemie biochemistry intercellular protein degradation lysosomes ligase ubiquitin proteasome ubiquitin-proteasome-system cancer drugs protelolysis Nobel laureate Ciechanover, Aaron
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Hey the you Vice-President Gideon of the Medical faculty dear colleagues and honorable guess it's a great pleasure and honor for
me on behalf of the Center for molecular physiology of the brain to welcome and introduce our guest speaker today Professor our intuition over from Haifa let me briefly introduce on chicken over to you to know a little bit about his CV he was born in 19
47 in Haifa his parents came from Poland as followers of the Zionist movement in the early twenties we switch initiated by Benjamin Hartzell around a century so they already came to Israel before the 2nd World War he was born right after the war and he was studying the nature as a child
already his father was a clerk in a law firm and later became a lawyer his father was a housewife and English teacher and his father always motivated him to use you huge library they had and our own also told me that he was reading books this very much fascination hybrid even more so he was interested in nature itself and you try to explore nature and there's a short episode that those books in the library
when it used by him always only for reading but also for pressing leaves and flowers and even even small reptiles so I learned that somehow this family not only appreciated these things because they're also holy books involved in so there was a very early priming of his interest further substantiated in high school later where he met inspiring teachers and got interested in
biology and biochemistry physics and mathematics nevertheless he did not study biology but decided to study medicine that was a compromise for him in several ways because 1st of all it allowed him to postpone his military service at that time and get further funds from the state to study and get a university education because his parents had died meanwhile was supported by his aunt and his older brother another compromise for him was because he got a practical education in a profession which was always kind of thought to be 1 of the ultimate ones to be a medical doctor
so in this year's competition he got 1 of the few places at the only university which offered a medical education at that time the us are in Jerusalem in 1965 and he started his enthusiasm for study medicine and the preaching in 2 years I understand the pretty good and successful but when he 1st had to teach to to uh treat patients you uh got the impression that this is not the final grade he would go because he was often left just with no treatment that you could offer to them the the so at that time there was an interesting possibility
offered in the medical faculty and which allowed him to do a master's thesis in biochemistry for 1 year and he took this chance and the started in 1969 to examine the mechanisms of fatty liver induction in a rat model under the guidance of 2 excellent biochemists backup part on the and Benjamin Shapira In is already you could demonstrate a passive and active role of an increased activity of phosphatidic acid phosphatase the key enzyme involved in the and try to search the best cases so this experience with
basic research during his master's thesis I think was important for him to show him that there are alternative ways in clinical medicine and it is translational research and in medically oriented research within medicine nevertheless he had to finish his medical as a teaching and he graduated from that school uh in in 1972 at that time the very young and talented biochemist Doctor of Rome Haskell was recruited to work the newly founded Faculty of Medicine at the Technion in Haifa and things are new that this new uh biochemist was recruited his thought he should approach him and ask for a experimental medical ceases so he asked him and he
got 1 but the topic was not very well defined at time as he told me so in between all these years he spent that time and the education the clinical departments he learned to switch back and forth and he also got the training of course in the clinical subjects In the time in the army which followed afterwords served as a physician on the missile boat fleet but also spent some time in the research and development unit of the army but he maintained tight connections with are from hash collect it continuously taught biochemical uh in the biochemistry to medical students during that time at that time the hash-code
group was mainly studying intracellular put your license and an hour and asking for project he often him to study a completely new subject which was 8 protein degradation system that has that been described so far so he was kind of left with a vague idea that there might be a system which has been described at that moment besides the lies homocysteine so in the following years he started 1st to do a training in search tree at the resident but realized that his real love was biochemistry and then he finally switched over to do this credit studies these are from hash Pashto and in these days they probably had the 1st ideas about how the system that you will describe nature of you Bickerton in proteasome system would work the in the 1981 he
you went to the MIT to work with Hari knowledge basically carrying out his own projects further so he did not go as opposed to a into another that and got another topic but he had better conditions to work but statuses topic during that time in 1984 after 3 years at the MIT of course as an excellent young scientists he got lots of offers to stay in the US and he was tempted to do so but finally decided to go back to Israel and the home country and are from hashed who again helped him to get an independent research position at the Technion in Haifa where he still is so the Technion has traditionally been a School of Engineering and the leaders of the Technion have not that being not much being exposed to medical and biomedical sciences and I learned that during these years the even thought about closing down the med school and only in the recent years they understood how important biomedical research and translational research as we can learn from our own experiments are for the development of new Europe's and of course offspring of biomedical research and especially those institutions which follow those the so we are glad
that are on was successful in maintaining the lab at vet school in Haifa that he is able to work together also with us in several European Networks and that you can carry out this through research furthermore as you know our and has received many honors and awards here several visiting appointments at the most distinguished institutions in the road like Harvard quite a Bush students includes he received the Lasker Award interest thousand in 2004 the Nobel Prize for Chemistry together with a from harsh to die he will tell us about important implications of ubiquitin-proteasome system but only for our understanding of specific protein degradation in general but for our understanding of cancer and also in Europe genitive disorders with the title which is indicated you while our proteins have to die we show so things again for coming to get union despite a few tight you looking very much forward to you think
thank 5 thank you must adjust for inviting me the pleasure to collaborative you for the last 2 years since we started in 1 program and what I'm going to tell you today and is in the very short maybe 45 minutes or so however long short 30 years 1 can go for a vague idea that basically doesn't exist and people don't believe into a user developmental for huge platform in biology but even more important or as important understanding of pathogenesis of multiple
diseases and the development of drugs so we have gone a long long way since we started our drawn into this black forest uh through the German term um air of of not knowing at all where we are going into actual blogs in the market and patients lying in hospitals and being treated so this has been a marvelous Johnny for me and I witnessed at all from day 1 I would say so and the mid seventies when we entered the field there was no field basically because most of the people the interested in how the gene on is translated into the protein and this was the post Creek show after so when people are interested of how the energy is there a replicated and how they can be amazed transcribed into RNA and how our is translated into protein some ribosomes and so on and so forth and nobody asked the question where we assume that single proteins and what happened to them
at the end and if people thought about it and they were very few people that told about the the cell devoted to some margin of side question is garbage in a scavenger and each other in relation people so all proteins have to be regulated they should be regulated to the gene expression level nobody so what about the other side they can be a revelation of the
other side and this was a garbage title for mechanism to do the plot basically in the attention very few groups were around so things of change and I want to tell you how they were changed so um the basic reaction of proteolysis is the same and it has been there for ever since people discovered
trypsin approach investment as amount trucked enzymes and it's taking the nice property
that has a that they belong and putting 1 molecule of water into it and making the formulas of the part if you think about protein synthesis the
opposite it's exactly that and in basically if you want to think of modern biology it's encompassed in this so you have
a slide because all the purpose of what we are doing within an I'm just putting tool and sodium foreign multiple amino acids together at the right order and there is a mistake in the order or something happens then we're in trouble but basically we are playing with molecules of water we are putting them we are either extracting them and generating the peptide bonds in 2000 or missionaries or taking them apart now if we think about
so that there was so important about
people you about trypsin penetration for generations than Y Y to go back into this question and the going back into this question has to do with topology with a hierarchy where it appears in the body and I use a lot of medicine during my talk and where we learned from medicine because it's very important so the
most primitive most simple I in a primitive at protolytic system is in the gastrointestinal tract where every is being there just with the proteins and we just it's non-discriminatory non-specific and the purpose is dual to remove antigenicity and to derive energy now once we have crossing the lining of the gastrointestinal tract and we're inside the simulation we immediately the different world we're world of control we cannot afford threats and all day just as I'm just going wild in ecting
while in the circulation and again if we look into medicine and you just to example where operations in the system lead to severe disease quote protolytic system so if you think of the blood correlations system with the ball of the the cascade of proteolytic events that 1 properties becomes active and activates the next 1 that becomes active and at the end hydrogen
is converted to fiber so think about the major killer in the West as the major killer in the western world myocardial infarction it's an and process obviously following relation of cholesterol you mitotic class but at the end coordination of as coronaries are occluded and part of the heart of all the whole patient is dying the to In the opposite of all set of genetic diseases hemophilia blood collision fucked was missing and that patients can bleed profusely form a minority injury and I can bring you many more protolytic system degree in the circulation the taking is of 4 1 and antitrypsin of on Qi and the hybrid trypsin and that lives there that the deficiency of them lead to excess of proteolytic activity in both is the mind to liver diseases and I can bring you are the multiple examples when the system goes along now this is the extra cellular now and once we went to the of things become much more complicated because the level of control and specificity that is
required in this is much higher than even in the circulation so why do we need to degrade our own proteins and again I know from knowledge to limit myself only to intracellular proteolysis why at all we need to degrade on properties and there are 3 main reasons 1 major reason that you don't appreciate may be and the less than a decade ago is quality control now that you start to understand mechanisms of this is we understand what's quality control basically all the nor the generative systems operations and quality control because we're collecting proteins that should be otherwise degraded so that's quality control problem you're accumulating different proteins that should be the so according to control has to do with the maturation of enzymes with misfolding of enzymes was mutated proteins that cannot be removed that contains all kinds of change that should be there and even simple things like proteins that are part of my the Subunit-Complex complexes not all of the subunits source-independent saying it CWI molar amounts then we need to remove excess of non-use and this sub units so that's also quality control of all the proteins are normal then we need to control a prosthesis so there's a normal proteins that have nothing to do them of 1 gram of misfolded but have to be removed at a certain time so you can think of any transcription factor that you don't need any more Nf-kappa-b meet false you can think of the entire cell cycle the whole cell cycle is riding over we more of
different regulators of different times cycling independent kind the site independent countries in the middle chromatid gluing proteins all of these proteins need to be removed at a certain time so the process can go on and then obviously 1 can think of differentiation and morphogenesis in order to keep the differentiated state and appropriate morphogenesis of organs wanted to remove certain part and so there will not be that they had been there before before Figure function into the tissue and make a decision and now we don't need them in so sorry good reasons why we need to degrade proteins now the extent of the sample that process is you would basically we are destroying the we're removing
daily 5 to 7 per cent before a protein it's a huge process quantity y and I can give you an example that is a C and and that that once it's accelerated if you take a gunshot wound the and the patient or you taken and patient in their hand in chronic infections or or or cancer induced cachexia the patients is losing kilograms of body parts in in in all time basically take a patient and he has a little bit of a favor and some infection within 2 weeks 10 15 20 kilograms of body
mass are gonna computing but even normally we are removing every day total sweet kilograms of 0 wait but we are still able to exchange the so the process is not negligible it's and major process now go to the history
because what I want to emphasize too is where we were in the field and I think this is a very with educational lesson because we we basically like any scientist I believe it or not familiar with the history of of
other fields or so much so we collected some stance so once we entered the field there were heavy pieces of knowledge there in lottery to do is to collect them to do so and tool to understand that something is the easier to add the missing piece but a lot of information was shown down the founding
father of modern proteolysis was world ocean liner you grew up here in Germany but then escaped Germany in the mid thirties when the Nazis rose to power in 1 to the United States the like many others including comic both and he ended up in the same department as common the Department of Chemistry in Cologne University that because they absorb so many Jewish
scientist became at that time probably the best Department of Chemistry and all this was the beginning to think of the rise it off American science and world of Shanghai there was not interested in science he was interested in methodology and interesting frost on that bench scientists they all the people the development of the but we don't realize that the math and science not without with it's hand-to-hand process and along with Harald way he developed of all kinds of isotopes and so great was the part at the time and they use all kinds of final built to study and to prison on all kinds of metabolic processes so cannot block was there any elucidated obviously the cholesterol biosynthetic and others elucidated other pathways and and and and no doubt the production line was given to the person behind probable they had many papers but very interesting story died untimely at at the default is and he is among the outline of its formative years and 15 this was a heavy isotope-labeled tyrosine and he gave it to readily founded the army unless it goes into the proteins and comes out so on and you for asking taking you for granted with so fine what's so what the fuss about experiment the fuss about the experiment it it was a contradiction to the program in the field and once they broke up with something that is not in line with the paradigm they're rejected so people don't take years to accept and the part in the field laws the proteins are stacked that they don't exchange we have our proteins we being born we assume that there's all approaches to the age of 15 16 whatever and then we walk with them through 7 8 decays and the we got the same very properties people really believe in this this city in the the fact that proteins are static and you will see the word of coming
from the events and there's evolution this Parliament and there but then now we are moving 10 years this was the early forties we already in the mid fifties will jump very quickly along the decays where the mid-fifties into very famous scientists Joplin all Noble
laureate himself from the Institute spare ritually many of you know him and don't know him and we know him because every day we're using the trait that the develop the trick their sophisticated method in order to reduce proteins in the theory by soaring ITG G into book theory I'm activating the local prong that's what the shock error in a story there is a common wonderful of food discovery and and they this know about the founding father of modern
an fly genetics now at Stanford and they started there's there's stability of but developed those it days in the fundamental about those it is
stable and then they went on to conclude for any other protein and they said that to some other since present to be no conclusive
evidence that proteins molecules within so from and pieces are in so of study and again the same all of our experiments have shown the protein's of equal our static so in the mid fifties people are coming and tell you tell the scientific world where guys there is no problem don't study anything because there is no problem you don't have to study degradation of province on not degraded the so this was an extremely influential paper I mean I I can understand those those of Europe a very few papers came out the scientific community wasn't that big such a paper was extremely influential and basically shut down the thing but meanwhile some leakage started around and 1 leakage was and a very obscure paper that came into the sea that attracted our attention later on showing that prompted the relation is an energy requiring which was very strange thermodynamically so here is just the release of labeled amino acid from tissue doesn't matter and wants to exchange atmosphere from oxygen to nitrogen you go down this didn't make any sense thermodynamically because proteins are like a of our like benzene like gas and their high energy regions we need them in order to derive and so I could put more energy in order to degrade so this did make any sense and it was kind of formal was what in the literature and forgotten from the heart of anybody and it took decades to reduce to rediscover and
then came Christianity is wonderful so biologists in the mid fifties also in he discovered the lysosome what would the presence of the mid
sixties and the life of the loan is a nice
organelle it sits in the cell and inside the surrounded by Member analysis inside there is a whole cohort of properties like exactly like in the
the gastrointestinal tract cathepsins in different enzymes and or read again here is the mechanism so people started to become the protein's are degraded and the only question was what is the mechanism and here is the
mechanism so this discovery basically with all its beauty and important shot the field again for another almost
25 years people got the notion accepted the notion that the lines of what is the overrated degrades intracellular proteins and they believed so for almost 25 years from the mid fifties all the way to the late seventies and how they
degrade the problems with extracellular proteins it was not a problem
micromolar more molecules like glycans of of receptors like India the famous work of Ron Goldstein and and an initially you pre-departure process and you can just scan mother in biology are being bound to a receptor on then they go and buy a clathrin-coated vesicles and a whole series of physical they go to the lysosome so the question of extracellular proteins that come from the outside was not a problem the problem or the game is the lysosome involved in the relation of interest proteins and answer that question himself and other people gave was yes How by Michael autophagy so here you can see a small micro autophagic
vesicles that consists of the site is also makes it bled here this is a nice little Michael rather makes a bled and then the contents of the blender being fall into the lysosome and then the it degraded but don't forget that this Bled contains every single protein that is in the sight of 25 thousand different properties the sitting in this book now if you do a simple experiment in the lab and you take any protein that you want and you mix In on what properties it will degraded human the so the process is not selective and then people started to this to to see that problem the revision is very selective and different problems have different stabilities so some properties leave only few men and some proteins leave many many hours 3 difference in kind scale which could never be explained
based on these micro autophagic blending because it's a total this Bled contains all the properties and so they should be the way to the same time so how is it that proteins are have different stability stabilities not only that but this time the enhanced and hot in allele and polymeric described the cell cycle another major development in biology and during the cell cycle proteins have the same protein changes its stability so cycling is very stable along most of the cell cycle but then degraded during my policy that's my talk excitement and you once cited this degraded due during G 1 so so protease also people started to realize the system must be very selective and the lysosome did not provide these explanation for specificity and they were other arguments that were coming some
came from medicine by by Brian pool Brian pull again I will not go into cave brilliant scientist at Rockefeller University he studied malaria so lots of knowledge came from medicine In the static malaria and as you well in Germany you don't know it but in my country we do more malaria and actually got it in several at times even in modern history and I it positive is is it is being written by chloroquine this is 1 of the drugs that is being it's that it's being used and and chloroquine has been known for years as Salazar's overly inhibitor it inhibits the lies long simply because it's a base the base is going into the lies Islam and there it neutralizes that utilizes pH from work of the of the life of them has a very low pH
interrupting inside the lumen of about 4 and a half to 5 which is necessary in order to keep the properties that they're acting in optimally it'll pigeon once you neutralizing entering the pH up the lysosome is basically dead so it's a very nice trick that you can use in many cultures so that the chloroquine into the middle of the beige analyzes on the shutdown so Brian did a very simple experiment and he
tested lies is on on the degradation of given x a general and the gentlest proteins or protein that come from the outside and he founded endogenous proteins cluster of proteins are not affected at all or almost all the public or open so they're get the like 17 % in 1 experiment 4 % in another but nothing really important significant when exogenous proteins for in that come from the outside are degraded by the lysosome because they can be the the relation can be strongly inhibited by chloroquin so he concluded
that he was this in my opinion Bryant poor was the most important researcher in the modern era because he predicted don't types of protolytic in this 1 is the lies along that would be involved in the relation of extracellular proteins because those proteins can be inhibited then 1 system that according to the name and I just read you how you rotate in a very poetic way and this is prophesy of scientist it's just really models I and what you want is the following
that don't let let's look at the distance of this from the exogenous for the exercise of proteins will be broken down in the lives of within endogenous proteins those that cannot be the metabolism of inhibitors will be broken down where everybody's that endogenous proteases are broken down during report internal wearing is no this is late seventies
this is 77 erotic and 77 and left it in the literature he died also untimely from complications of diabetes and other diseases it but he knew that the center is equipped with that another system that he called wherever and we enter the field exactly the time I became a graduate student without run our most at that time came from post-doc
he was very young scientists and I was his 2nd right isn't that you to graduate students starting in a meeting room and there and the levels very poorly just started a lot animal and and will support them because it Italy yes they have a subject for you but the subject has only a tighter the title will be we are going to find together assistance the degrade it is not normal and grades in dependent manner it was similar proteins in said OK of RAM what is the system that I don't know what is it must exist and we're going to discover so we really started from scratch and and you see the whole people start from scratch and I like the idea of starting from scratch because we really had no clue and to start from scratch at the time that there is no
genetics and it's not too long ago you know people think that were born into generic with that time there was no
genetic was these genetic yes and some elegance genetics but no mammalian genetics no etc. nano antisense normal in flock no nothing we had to to use nature and nature provided us with a wonderful cell and this is the article such as the maturing red blood cells in the bone marrow and you can induce lots of vertical poses oven is a physician and position myself so we knew that patients with anemia have reticulocytosis in the peripheral abroad so or 2 billion reduce anemia in the in the in the rabbit and the bomber or porous consul vertical sites into the circulation and there is the beauty of the article so that it doesn't have minds the
we need the so without the lysosome because of very sneaky and nest the enzymes that would be great everything around and you need to work without the background and we needed to work with all the background of of properties and we use the radical sites and in no time we
published the 1st paper in a very awkward jornal which is another lesson that John was really don't matter this this paper cited more than 3 thousand times the
cannot immediacy and it became the probably the most not only the 1st of the most important paper in the history of the field that now has close to a hundred thousand years so in this state what we found is
the following we found exactly what we want we found at high speed supernatant the excerpt of the cell has an ATP-dependent activity degrades global wheels global artificial subset doesn't we later on we expanded the the paragraph or a subset norms we just so it and it was another very important lesson in this and I will not take from biochemistry at all during the lecture because I want to pop quickly into medicine n we had little fraction so we don't realize at then we fractionated biochemically another fraction head in activity of its own but we had to recombine then we know that did and this was a very fruitful lesson because it was also a shift from a part that the part in the field was that you the protons and a subset so unit for this wedding to only 2 units for this town and you it 3 door fractions 1 and 2 and the subsequent so since disapproves subset of fractions if you need rate if you need to fractions maybe you need 20 because the called fractions and maybe you need to 100 what I can
tell you that is the following the mother and biology of ion discovery by unraveling of the human genome so that the ubiquitous system is composed of 1 thousand and 500 enzyme they're not mediated altogether for the grading every protein but altogether it's the largest known family in the human gene once it's 7 or 8 per cent of the total human
genome depends how you look at the data look at the genome having only 20 to interview you only 22 thousand 700 proteins talking spicing products there at the so receptors and antibodies into a conclusion that really
hard hardcore projects 7 per cent of the total human genomes occupied we 1 system so the hint was already a lower confidence now let's go to what we really found and what we found is something that was
again change in Part I wanna go into the details of what found is there In order to destroy a protein we need 1st to it we need to put on only some kind of a tag and the downstream
properties we not recognize the UN protein so it's a two-step mechanism taking like you can imagine that it said the court system in democracies so you do we don't catch criminals in the street and shoot them with data to the court the court decided then we execute that the punishment so to post that process now I don't bring this metaphor just for their their humoristic part of the but I bring this metaphor because it's an anal scientists to explain how the properties and the substrate can live peacefully in the same compartment which is the site of of because properties is active properties can never leave with substrate in the same compartment in the gastrointestinal tract we don't care we Wheatlands we wanted to be the edges so that we don't care in the simulation we don't care we
activate the properties only 1 with its own we get 1 then we have to be the blood compilation system we don't need the blood collection system to be active before it would be the deleterious or and this it was act a correlation in in it during the normal circulation can bring you know it's the holes in our whole course in in the mythology what happens so soul in the lies on on salt gave people this kind of the thinking relaxed thinking that the problem is that because the length of his the membrane so the problem was for the subset of X with a memory but the light on a pro-business never see
the substance of that the weights for the sort of the properties and here for the 1st time we provided another form of post-translational modification taking by a protocol DAP of 1 electron turned out to be weak within doesn't matter amenable to the history that the only substance authoritative are being degraded by the properties that
we now know is called the protozoa ministries it's a it's a it's a huge structure that I will tell you in a minute it became a drug target and and so on and so forth so it's a it's a technical who take a protein and the sub and taking the subset to be degraded then that and detecting protein and we make a conjugate with tags and only then the protease common releases in and then detail with cycles back into the system so
that and we know it already 1980 so this was a completely novel idea we're going to the different orbitals have to understand the for understanding
this so this is the taking the garrison of going to the chemistry that didn't chemistry is the substance of that lies in residues that lies residue by nature has an epsilon amino group and we are
generating this very strange post translational modifications and the protein that is bifurcated it'll never heard of proteins that becomes tagged by other proteins and and and and that they look like a fork to you see here this is the handle and this is the
4 so this is this this this thing that to be degraded and now the protein comes to an and and and text but it doesn't come once comes several times and I show you how it comes it comes several times come once so this is the 1st thing and then the the 2 the 1st taking become set by the 2nd 1 and then it indicated goes to the start time so the 2nd is being attacked by
the 3rd and we are being what we call the Pawnee ubiquitin change so the tag is not a simple unique that it's support that and the properties we recognize only the politics of this also called most Spain for biology that will be very hard for them to accept and to and for us to the cipher but nevertheless it went so and the properties which is the 26 this is only recognized only
these they have lost and we have recognized just the naked eye and it stops which again allowed the
shock and debate to live peacefully in the same very compartment was of the essence of the whole system and which explain the specificity of now and and not only that my understanding this thinking mechanism which took the problem of free because until then the problem was with the properties what is the mechanism now the problem is that the properties of the problem is always the ones to be tagged
when why and where so the problem or upstream along the system to a complete different level of thinking so there are many lessons in this the type and the
properties is it is important that the parties will do the same for all the properties if you take every properties that is that way we could integrate so in that sense that maybe it's less interesting it's still extremely interesting them that but I'm taking away toward but that the problem of specificity in recognition move up hallway declared they warned when where and why so this is their mother in
ubiquitous system and then just show you in in a snapshot and then we go to med quickly to medicine so here the substrate we so this is the target it's like a Greek like would uh ball in this case it has to be phosphorylated because
this is again something than not just degraded they have to undergo something in order to recover In this case it
would be phosphorylation and it would be recognized by an enzyme called ubiquity lighting you because light is why because it like gates the tag to the south and there are thousands of these in the database thousand
ubiquitin-like is the 1st sitting at about the base waiting for the different subsets in parallel the ubiquitously approach you want there was only a single the 1 in the
database in the human genome and ubiquitin will be activated by E 1 it's going to be in activating enzyme will be transferred it's like a chain reaction there are some reasons for this attenuation energy transfer not going to it the specificity 22 which is going to be within carrier protein and there are about 50 equals in the database and then bank so the text will be there so the project is now going to die but it's not that the and it's still reversible we can still take this 1 away there is still a possibility along the chain to take this 1 was for the system is flexible it's they didn't make the cut because if we put 1 cut into the probing the proteins that become group again we have to will bear by entire for their synthetic machinery and now comes the big beasts the 26 ozone we by the chain we unfold the protein and we take it in and spit it out in pieces so that's basically the system and the
core part is recognition this is a very most important part of the system that the binding of the
recognition in the light of this initiator the entire change so the the this is the system other systems
article effectively and that's very important to understand for medicine resisting
150 those thousand the phrase immediately we recognize it very limited subset of substrates and we
ubiquitinated then and then the proposal would sit here so that you can imagine that the system is the diamond shape data the top tapered at the bottom
of why the media now immediately if
you want to run the system to use it as a drug from you immediately want to do it here in the
broadest point why because the most specific
point it don't go side effects and so on and so forth so no doubt that this is the point well that it's not simple to belong to this point and we evolve this idea of probability of the system and how it's related to the this and the next human
meanwhile happened is a very and enriching their development that we were not involved in the heat at all Wheeler pushed to the side completely we're almost forgotten and put a ubiquitous the relations signal became just 1 function of ubiquitous so we are here now without discovery you want to with 3 polyubiquitination photos on degradation but then the world became much richer and people discovered ubiquitin-like protein so frog America was no happens to be here in university which was a postdoc was large arrays Santiago discovered so which is small motivated modifier and if it's a Ubiquitin-like protein that is activated like a big that it modify floating only once it has these green proteins find its destination to the nuclear pore complex otherwise is green 1 want in the cell and we not laudable it's a major problem in this set is a trophic there's no GPS and so so we have to provide all the proteins was GPS more GPS machines so that we know where to go and do some always a kind of familiar GPS for this green propping will you n cell surface membrane proteins are all include agglutinated and then they go to the lysosome then you and and
ubiquitous itself has several lies societal deubiquitinase ubiquitinated himself itself formalizing residue which lies in 48 but a civilized so we
can be different chains so the change that what what what we got now basically without going into details and and here there is monoubiquitination so we we we we can go to polyubiquitination we can go to all legal and we can go to model and we can go to sumoylation which is other
proteins and we are now in yields world of of phosphorus another form of course translational modifications that is extremely rates because it made by the project and as you know proteins have lots of variability with their other family members and lights and and and there is it allowed the system to acquire huge
flexibility so for about 10 years ago would've been asked what is ubiquitous I would have said ubiquitin is a degradation signal now I would say that we could use a passport the passport is a document that allow different passengers to go to different destinations so if it's a certain polyubiquitination it's the possible to the protozoa is a different polyubiquitination to profit for activation of transcription NF-kappa B is activated by polyubiquitination on different but different chains of the chains of very different uh it's of some ways of possible till run given equal to the nuclear pore complex and and bracket 1 which is a very important properties more involved in breast cancer uh a tendency in woman Morocco want deubiquitinating air is the ubiquitin like that to be quickly from quality protein which is involving Franconia meaning that is another malignant inherited malignant disease so it's it's ubiquitination so many many different functions in the cell and and degradation is just 1 of this so we became a member who so that we have a family but we were went wrong we're just members of a large and we are not the famine now let's look quickly to diseases and this is the
development of the last 10 or 12 years and it's a fascinating development so normally we can imagine that this and I am now going into the is I will again focus on proteolysis because the other members of the family of the having said the final word but there clearly are going to be targeted we can imagine and no assignments several scientific advisory board of companies people will target the other function but let's go back just a product so
this is the ubiquitous isn't injustice came importance of greater than they are in the steady state whatever can be static steady-state in an extended state but they're keeping the green box up problems cannot yet In the protein would be over degraded so which we go below the steady state and this can happen let's say that the light is going
up in an uncontrolled manner that the ubiquitin-like is the deubiquitinase the problem we all
of a sudden be expressed in uncontrolled manner and we take a protein down and I show you 1
very prevalent example walk something can happen here
and the ideas will be mutated or the substituted in the protein we look you so both cases have happened then let's they cancer as a case
of study this Council has been really extensively studied there is a model for the ubiquitin system actually the 1st glance the the 1 that is in the market advantage when the sun in the market there are all kinds of drugs so again but we have again I want
to read to understand 1st review cons so different diseases result from operation due to the demolition of different groups of proteins is there will be a problem with quality control if we
select this is typically the problem of under the relation if we don't degrade project that should be greater their Q 1
operation the relation of quality control we typically to more degenerative diseases as we know them now and to some accumulation diseases
and delivery monitoring the the monitoring bodies diseases and so on but mostly the quality control we belong to the brain and we we see that the hallmark of many neurodegenerative diseases in genetically acquired or sporadically constant is this is accumulation of some types of proteins are not always related to the system but many of y if we're
losing control of processes at 3 mostly in Wisconsin because it's what typically will be an oncogene that is activated and or degraded and so on can be typically 1 for and let's say the differentiation will morphogenesis we typically to genetically and this is what 0 0 I want positive book about this whole so let's go and this is obviously 1 example of the of the
taken from from a patient that have some operation deubiquitinase systems some missed transcript of ubiquitin system and they suffer and and uh I out some of
but but let's to comes this Council would be much easier to understand so if there would be an increase degradation of a tumor
suppressor like 53 who would become so because the so be exposed to advantage they 53 is the ultimate genome garden it the
sense are basically you know we are we are we are in a murine which we're talking the language of sound source we are interested in some cells and if it histories
the ultimate damage census there will be a damage to the cell the sensory we jump up we stop cell cycle we try to repair the damage and if the damage will not be repaired the sensor we can the set we send a and if history has been associated now 1 way or another was almost 80 or 90 % of all kinds of it is mutated in 50 % is normal in 30 % the then its metabolism is operated in the 3rd person so effectively that critical at molecules so obviously he could degradation of
the 53 strictly 2 kinds I can give you 2 examples real example what is the human papilloma
virus the kids do you live in uterine cervical carcinoma in woman and the this is the virus that is directly associated with this malignancy and this virus can cause an oncogene called the 6 the 6 combines the the 53 generates a heterodimer with it free ubiquitin system that is a quality control system this leads to think that this intricacies of because it's no literal dimerized with another foreign protein and we jump on the system integrated and it will be greater than labyrinth manner using a light is that we never recognized at 53 actually this like is is a very interesting ideas from and or logical point of view it's called the Sphinx API 6 associated protein because it X with the 6 to the great it 3 but you can imagine that blob or whatever was in charge of
evolution depends on our view personal view did not involve is 6 AP in order to be great if it did not avoid involved is succeed in order to be great if into calls woman that we cannot suspects Our created to be that all that militias so it's it's a was created for something else completely and didn't described aberration what happens with the 6 EPI is it simply is a protein that when operated leads to a very severe genetic neurological syndrome called elements in the kids are are born with a severe and mental retardation they have this of Urological syndrome they're walking on the why did they laugh out of content quality context and them so the idea how with this disease is and it's a close relative of another and another disease in which people have an increased appetite for brother with a single and it's it's close link to a
genetically a we're not going to live so they be however it with their endowments in with his mentor oxidation is that you have a different in like is that meant for from other software since the light is is defective some protein accumulates in this project is more toxic and the end of this
multiplicity is the Andaman single it happens all the the viruses which are very smart adopted the 6 be also to 53 during HBV human papillomavirus infection of the you trying and assume cervical indices so it's very interesting kind of complex linkage now so this is iterative frame it's been degraded there's no you there is no June garden and the virus can integrate into the DNA and and and and and local transformation the opposite is oncogenic brought in oncogenic properties our normal practice and
almost all voting proteins in the body have potential to become oncogenic if over active so big data pertaining that that's in our contestants once it's it's it's it's fair to becoming over active it's not degraded to induce colorectal carcinoma they the EGF receptor that was truncated an over active it's not regulated anymore more willing to on and on and on signaling and at the end will lead to breast cancer so this is the 1st urinal cancer some of them are susceptible to receptive to the new 1 bodies
so even under degradation of oncogenic proteins or the relationship of the the concept so we don't have multiple just examples I think that we were related to understand the knowledge flow 2 blocks knowledge so I want to conclude the talk like that telling you that we are dealing not with the hours revealing with patients so the best place to put the drug will be here as they call you but the 1st run was not developed this the 1st blood
surprisingly was developed to the protocols for many reasons I don't like to the reasons 1st of all it was very easy the problem is a properties at the end so it's very easy to develop drugs a protease inhibitor of there are many in the market they had been before people know
exactly the structure of the active sites of proteins this and it was very easy all
that they had to do is to make it specific to the proto so that they can relatively nonspecific and small molecules and to make it a high efficiently highly efficient high-affinity highly specific and that's what the company did it's a Boston-based company I have nothing to do with a company late development and the graph is called P 3 4
1 0 5 OK or what as a lead
well you know it was a it was approved by the FDA 3 years ago and then it's have you know in many cancers and 1 in particular that I'm going to show you it's a single that
tied in see with the boronic acid relative in its local physically about 3 only in the
active learning residue in the active site of the problem so the mechanism will work out literally and we know exactly what it runs the molecular and here is a patient is is the blood
and here is the patient with multiple myeloma just for those of you are not talking medicine only multiple always a type of a
leukemia so it's a model similar extension 1 cell becomes malignant plasma cell the provinces other cells in our bodies to generate antibodies but we have different plasma cells we that is the a father so that that that that they that encompass that constitute then prior immunologic repertory basically we're to can less ourselves against every single potential OntoGen that'd be some some playing some extra from plants in Australia that you never been exposed to whatever antigen that the beautiful work of that door Burnett optimal the prize in the sixties unbelievable and beautiful work too but in this case I think it's cancer so it's 1 plus same extends in an uncontrolled manner in this 1 level so can secrete 1 single immunoglobulin in this space and it's a woman it
is a great idea of the beauty of this this
is not for the patient is by the beauty of this this is and the green off every oncologist and physician but based on the body is a biomarker so we can take a small sample of the blood and look to the biomarker and the more we have the better the boss is the situation of the patient the less you have the more suppressed is the total but very few toss unfortunately handful or less are secreting such wonderful biomarkers its degree no more than spectrometry and high-protein resolution is defined in the blood biomarkers for different kinds of that we need very very sensitive detection systems like we need for everything I still away from the so you can see this is
galloping you started their regular chemotherapy mouflon not real my syndicate wrong whatever the fuses the oncologists know-how to poison the patient and is the disease is response partial and then the disease relapse this again has started the treatment of the A 3 4 1 and the is received and the don't that but it's not a miracle I mean this is a rare patient and not all patients respond in the question would be what the respondents on or not but it's no doubt the revolution in this improvement of this is this is a deadly disease patients are dying in
agony In total 3 years because the the the bone marrow is taken completed by the plasma cells so all the other blood progenitors are gone suffering infections correlation problem because of lack of Trumbull seismic parasites some not the and and then the bonds of being broken because the the the the door presses against the that against the ball and the ball rolled practice in the vertebral fractures in in the long
bond and because of their of their this a protein a renal insufficiency precludes the trouble I in the in the kidneys it's a very bad is very but is and here the patient response and you can see bond where all of the patient and again without going into oncologic is the pathology you can see the major difference between the homogeneous malignant bone marrow before the treatment and the blue almost normal bone marrow that the that the note that says the malignant cells went down from 41 to less than 1 % which is no repopulated with the normal bone
marrow progenitor of the red and white blood so you see that the patient is being helped and the patient is still so if patient going to mission the task for for many of us here is another patent this is a
cat scan of the you can see it the sitting here this is a ontology form but the was sitting here in there in there right you will in the view of the right lung and the total received by an order from it laughter single-site now since the drag comes
from a different world is chemotherapy in combination with chemotherapy modest therapy it's extremely efficient and they indications are broadened I would say date but every month they see a new data paper coming in the New England and in cancer research in the Journal of the NCI of new indications so far and concept that was completely resistant to any part of the name of the disease is now being treated successfully again not all cases if you're Akershus and not here to advertise otal spread any uh hopes but but but it's in all approach to oncology because it's coming from not from the DNA culating not from Ivory imizing indoxyl will receive irrigation it's coming from a different system and
therefore it holds by itself and with combination and but the future
now let's go to the last section of the future is in rocks it's not in proteasome inhibitors it seemed like his inhibitors and I want to go back to be 54 because it's really in a proper model so that all you every stress to the cell DNA damage at the lower shortening their oncogene activation
me immediately to the increasing the 5th straight abilities really ect along time very important for them as I told you to do all sorts activities in
a time is needed to stop the cell cycle because the so cannot proceed for 2 divisions with air but then as it attempts to DNA repair and if not it induce a proptosis let's leave alone so in a sense this smooth 16 and poly components of that's much more complicated around too willing to but in although growth arrest and DNA repair and if not then now so that
basically given 3 oncogenic stress if if it is 3
to inhibit cancer we can Europe simplified and this simplistic scheme is basically correct now this is the
phrase psychosis with its own ubiquitin-like it's very interesting so given the 3 the transcription from were transcribed many downstream genes 1 alleging that the transcribers if only ecution so 1 of the few tionaries up 53 be down it to be degrade now once they've face degraded it will not be able to describe the execution so they the Commissioner we'd be down that if it is really be up again and this will be up and this will be done so with cycle and
given measured in the the oscillations between the 53 in its on execution of very simple servo loop mechanism simple oscillation and that appears all the time now 1 there is
oncogenic stress something happens this is the 3 of the most phosphorylation acetylation and becomes resistant to the HP into and then it goes up because the until we also go up but it will not affect the 53 anymore because if it is really that there would be an aberration in
recognition the circulation and phosphorylation we operate with abrogate the recognition and this will allow people to 3
now to make and blocked evaded non-stringent Boris cell cycle to believe in DNA repair and to induce apoptosis if
necessary so this is part of the oncogenic stress that
immediately upon induction of a stressed give it a free must become resistant to its like is through the execution of
so it would be able to go up into the what it wants this otherwise it will be greater so this is part of the normal response knowing cancer in
some of the Council's where a lot of the Council's 30 per cent of 25 per cent of all kinds of something very bad happens then they would be quick and like stopped for response the age being told that the light of 53 stopped corresponds to the oscillating
control mechanism and it goes up and doesn't care about anything just over if it's expressed it will bring the 53
down so privative free will not be able to act once need and there because there is so much
of the agent to but it would basically suppress everything in the acetylation in the phosphorylation process will not be efficient anymore in in light of this portion of of the input I want to go into it was a test of those quantity of how much of the 53 is being but that's basically what that basically the light
years has become an oncogene by what they turning down the tumor suppressor so ideally you if we should be able to inhibit this interaction so I can do is to go out went down here by activity but we should be able to inhibit the activity of Indian to over people to
free which rescue the system the so all that is needed from the company from a company is to develop a small molecule that inhibit
this enzyme specific in it before then can
be high but it would be enacted and that's exactly what Russia's doing they develop protein
and small molecule called knocking code not in
because it was developed knocking jersey where the headquarters of the fate of the company is and what matters is
doing it's a moderate drop it it's not a drug that came out of high throughput datasets it's a
drug that came out of modern biology of understanding the three-dimensional structure of a protein this is a medium this in the
pocket that bind 353 Anakin was planned to occupy the pocket so it's a specific inhibitor that
competes out a 250 frame and we looked at the goals so it's a very specific a small-molecule inhibitor or
and you can see the result and that would be very almost the very end so we add lacking the 53 is induced this is inducing also its own execution abundance the fusion cannot keep efficiency because the fusion is 1 because nothing is always wrong to inhibit and the fact is that if it if they can induce very effective cell cycle inhibitor local P 21
so it's an active 53 and all those occasional is around it so that the fusion
then there is out there 50 % of 45 per cent of the so that used to cycle deploring in the S. phase in presence of multi out 5 % on it so they don't think that there's been anymore and there was a tourist so we're from there from the S. phase into the G 1 or even G 0 phase of the cell cycle and the resulting eyes this eyes here is the 200 close control to modern grows in treatment was knocking exactly like pretenders doxorubicin which is a DMA culating highly toxic cardiotoxic agent have the same effect the the the and the growth of the 2
so what we see now is a shift from non-specific drugs that inhibit the prop goes on in book a very specific drug that can inhibit and look at very specific possible and I believe that this will be entered the future of the area of the system so just to save the people and the foreign thinking that people are not go over the list of distances point out some important is just to tell you that about less than 30 years ago it actually exact authorities were suddenly appear be looked the 76 we started with so I started with a mantra that had no idea where he goes he could define assistance and I think that there are about 5 years ago it was a turning point in the 1st round was approved and them and
we are now in a computer different here so you see how things are evolving but we should take it all the accreditation take half of the presentation they given a quarter of the credit we added a layer of understanding but basically we knew when we entered the for the proteins are degraded that Shanidar we know that it requires energy that Simpson we know that it's not lies on that's Brian poor and all admittedly collected all this information and we conclude that there must be something as and we went into the something else and then other people came and added this information I think that the entire pathway if you really want to be fair to the
system talk about 70 years to get to the point and we played the role of some in the late seventies and early eighties and added our
only here and just think of the city of Rome and early of most my direct mental only played an extremely important for in the middle
he he really the cipher the the type
of bond that to be put is making and a polyubiquitin chain we had no clue so physicians know about particular site but they have no clue protein chemistry we needed the good protein chemist in the middle so on profit and the not for to on not the this gem fast and then I enjoyed an extremely fruitful period of harvest and lab and basically not only a good scientist that helped me a lot with my question at to give a complete freedom and was completely free to do what they wanted and at that time I collaborated Alex and that outsource assessed and then in philly at MIT and we found the 1st mutant of ubiquitin system because this was important to show that the system is not unique to the article side but is rather universal so this was it wasn't a breakthrough but it was a further important cooperation of the concept so this was a very fruitful by was the possibly 1 lab corroborated with another lovin there also able to move freely along the MIT corydoras which was wonderful and then many many postdocs and graduate students but there some of them are still
there and keeping all my lab at the so thank you very much and
thank you so thank you very much for this wonderful
and fascinating lecture I have a small book and it contains the kind of you uh honorable person here in getting in on the day that it here so that all of the vise of by year but you included and things again with this lecture I must say and you did not mention of course the other part of the UPS system which now comes into our mind and this is the protein aggregation disorders which we have to face so this would be the future you address the kind of each part which is cancer treatment has now we'll go in the back we have to use your help in order to address the more complicated ones and that is to treat the today the often the day I forgot to mention to treat the aggregation disorders which will you have no point the people do not buy from and things of this again very much for this wonderful that proponent of hitting and you
know you